WO1995028938A1

WO1995028938A1 - Molten granulated sucralfate preparation and process for producing the same

Info

Publication number: WO1995028938A1
Application number: PCT/JP1995/000753
Authority: WO
Inventors: Katsuya Matsuda; Koichi Ozawa
Original assignee: Chugai Seiyaku Kabushiki Kaisha
Priority date: 1994-04-26
Filing date: 1995-04-18
Publication date: 1995-11-02
Also published as: AU693545B2; CN1081921C; ES2173183T3; DE69525620T2; CN1147203A; BR9507533A; CA2188785C; MX9604994A; EP0759300A4; EP1110540A1; AU2224695A; EP0759300A1; CA2188785A1; EP0759300B1; US5718923A; KR100264547B1; DE69525620D1; ATE213635T1; KR970702053A; TW350773B

Abstract

A sucralfate preparation prepared by melt granulating a mixture of a sucralfate powder with a water-soluble low-melting wax; and a process for producing a sucralfate preparation by atomizing dry sucralfate, adding a water-soluble low-melting wax to the atomized powder, and heat melting the wax to effect melt (fusion) granulation of the atomized sucralfate. As compared with conventional sucralfate preparations, the above preparation is reduced in the size of dispersed particles, has a high ability to bind plasma proteins, and is remarkably improved in administrability and a protein-binding capacity.

Description

溶融, Η Melted granulated preparation of sucralfate and method for producing the same

[Technology] +

The present invention relates to a sucralfate preparation and a method for producing the same. More specifically, the present invention relates to a preparation and a production method produced by melting (adhering) and granulating micronized sucralfate using a water-soluble low-melting wax.

[Background technology]

Sucralfate is a basic aluminum salt of sucrose sulfate, and is widely used as a remedy for peptic ulcer, which has a substrate protein protective action (gastric mucosal protective action), a gastric juice pepsin activity inhibitory action and an antacid action. I have. Since sucralfate is water-insoluble, the disintegration and dispersion of the sucralfate formulation is important for effective binding to the ulcer site.

Conventional preparations of sucralfate preparations are made by adding additives and water to uncrusted sucralfate powder and drying by heating (spray drying), or by adding additives and water to undried powder and granulating and drying. Had been These preparations were mixed with additives and used as fine granules, or compressed under pressure and used as tablets.

The conventional formulation contains large particles of sucralfate, and the fine granules prepared from the formulation have a taste derived from aluminum when taken, a feeling of roughness due to the large particle size, and sticking to the oral mucosa such as the throat. There were some problems in taking the drug. In addition, tablets have a large particle size when disintegrated after ingestion, which is not always a favorable manufacturing method.

Considering the binding effect of sucralfate to protein, which is the main use of sucralfate, when applied to living organisms, it is medicinally advantageous to increase the surface area and increase dispersibility by miniaturization as much as possible. . On the other hand, sucralfate has the characteristics of strong cohesion and low wettability. In particular, if the sucralfate is made finer, this property tends to become stronger.In the conventional preparation method of adding additives and water and granulating and heating and drying, water is evaporated. Because kidnap ffi becomes large, It has been difficult to produce a formulation that can be suspended and dispersed as fine particles.

[Disclosure of the Invention]

An object of the present invention is to provide a sucralfate preparation which is excellent in ingestibility and which can be applied to micronized sucralfate to a living body, and a method for producing the same. According to the present invention, dry sucralfate powder obtained by a conventional method is further added to a finely ground sucralfate crushed powder, mixed with a water-soluble low-melting-point resin, and then heated to melt (adhere) and granulate. Thus, the desired sucralfate preparation can be prepared.

The dried sucralfate powder, which is the starting material of the present invention, is prepared by, for example, sucrose by the method described in JP-B-44-116173 or JP-B-4-171637. A sclarfate undried powder obtained by allowing basic aluminum chloride to act on a polysulfate salt is dried by heating, for example, spray-dried. For example, sucralfate specified by the Japanese Pharmacopoeia can be used. .

In the present invention, by further pulverizing the sucralfate dry powder, a finely ground pulverized sucralfate powder can be obtained. The sucralfate ground powder may have a particle size of 50% or less and a particle size of 90% or more, preferably an average particle size of 20 // m or less and a particle size of 50 m or less. The proportion of particles having an average particle diameter of not more than 90%, more preferably not more than 10 / m and not more than 50m is not less than 95%. The pulverizer used in the pulverization process of sucralfate is not particularly limited as long as it is a model capable of obtaining a particle size of 50 m or less, for example, an impact type pulverizer.

In the present invention, the water-soluble low-melting-point resin added to the pulverized powder of sucralfate is not limited in molecular weight, degree of polymerization and the like as long as it has a powder form and a melting point of about 80 ° C. or less. For example, polyethylene glycol, polyoxyethylene-polyoxypropylene-glycol, etc., or a mixture thereof can be preferably used. More preferred water-soluble low-melting waxes include polyethylene glycol having a melting point of 40 to 70 ° C, for example, polyethylene glycol 400 (melting point 53 to 57 ° C), polyethylene glycol 600 (melting point 5 6 to 61 ° C) or polyethylene glycol 2000 (melting point 56 to 64 ° C). The wax that can be conveniently used in the bath E must be solid at room temperature because it is mixed with the sucralfart powder in a dry powder form before melting.

If the box has a high melting point, for example, exceeding about 80 ° C., it must be heated to a high temperature during granulation, which poses a problem in handling. Further, at such a high temperature, other components may be adversely affected.

The water-soluble low-melting point wax is usually at least 5%, preferably at least 10%, based on the weight of the ground powder of Sucralfate, and the surface of the ground powder of Sucralfate is coated with a water-soluble powder to improve wettability. Any amount is sufficient. For example, in the case of polyethylene glycol, it is preferably added in the range of 10 to 20%.

When a hydrophobic wax is used, even if granulation is carried out in the same manner as in the present invention, a preparation having a large dispersed particle size and which can be suspended and dispersed in the intended fine particles cannot be obtained.

The heating temperature in the melt granulation (or adhesion granulation) step of the present invention may be at least the melting point of the water-soluble box used, but the temperature of the drug substance is 5 to 5 times lower than the melting point of the water-soluble box. Heating is preferably performed until the temperature rises by 10 ° C. In the present invention, in addition to the water-soluble low-melting wax, excipients such as saccharides such as lactose, mannitol, and sucrose, conventional flavors, sweeteners, and the like are appropriately added, and together with the pulverized sucralfate, Can be melt-granulated. The preparation obtained by the present invention can be used as it is, but it can be further formulated into fine granules, tablets such as chewable tablets or troches, capsules and the like by adding necessary additives.

Hereinafter, the present invention will be described in more detail with reference to Examples. Note that the present invention is not limited by these examples.

Example 1

Sucralfate dry powder (Japanese Pharmacopoeia) was pulverized with an impact-type pulverizer at about 3,000 to 3,600 rpm. The resulting pulverized sucralfate had a particle size of 100% or less, an aluminum content of 19.3%, a sulfur content of 10.7%, and a loss on drying of 10.2%.

As a conventional wet granulation method, 200 g of hydroxypropylcellulose (disintegrant) with a low degree of substitution was added to 4.0 g of sucralfate powder and polyethylene glycol. The mixture was kneaded at 400 rpm using a stirring granulator (manufactured by Okada Seie) while adding water. After granulation using a crushing granulator (manufactured by Okada Seie), drying was performed at 60 ° C for 60 minutes using a ventilation dryer (manufactured by Fuji Baudal). Next, as a melt granulation method using hydrophobic resin, 2,000 g of sucralfate ground powder was mixed with a hardened oil (Lubric wax 101, Freund) at a rate of 400 g, and stirred with a jacket. The jacket was heated using a granulator (manufactured by Okada Seie) while stirring at 200 rpm, and granulation was performed until the temperature of the powder layer became higher than the melting point of the wax.

Furthermore, as a melt granulation method using a water-soluble resin, 400 g of polyethylene glycol 6000 or 2,000 g of pulverized sucralfate powder or polyoxyethylene [105] polyoxypropylene [5] glycol (PEP 101, , Melting point 50-54 ° C) at a ratio of 400 g, and granulated in the same manner using a _c- laser diffraction type particle size distribution analyzer (Nikkiso Co., Ltd.)

(Dispersion particle size) was measured, and the average particle size (cumulative 50% particle size) and the ratio of particles of 50 or less were examined. The results are shown in Table 1. -[Table 1] Dispersion particle size

Granulation method 1 Addition ratio Average particle diameter 50 ra or less Wet granulation 1 Water solubility 23.8 xzm 82.9% Melt granulation 1 Hydrophobic 25.6 78.6 Melt S4 granulation 1 Water solubility ( 5.100.0 Melt granulation-water-soluble (e. Reoxy I-ethylene-ho-lioxyf ϋ レンレンク 'リ）) 5.2 100.0

(Sucralfate pulverized powder) 4.4 100.0 From Table 1, the conventional wet granulation method or the melt granulation method using a hydrophobic resin has a large dispersed particle size and can be suspended and dispersed in the target fine particles. No formulation was obtained. The dispersion particle size of the formulation obtained by blending a water-soluble resin with sucralfate and melt-granulating was similar to the particle size of the pulverized powder of sucralfate, and the ratio of 50 m or less was 100%, which was good. Example 2

Mix 2,000 g of sucralfate milled powder with polyethylene glycol 6000 at a ratio of 50 g, 100 g, 200 g, 300 g, and 400 g with a stirring granulator equipped with a jacket and rotate at 300 rpm. Melt granulation was performed until the temperature of the powder layer reached 65 ° C. with stirring.

The dispersed particle size was measured using a laser diffraction type particle size distribution analyzer, and the specific surface area before and after granulation was measured using a nitrogen gas adsorption type specific surface area analyzer (manufactured by Shimadzu Corporation). The results are shown in Table 2.

[Table 2] Compounding ratio Dispersion particle size Specific surface area Sucralf 7-to: E 'Liezalenk' Ricol Ratio of average particle size 50 m or less

100: 2.5 D .8 90.2% 2.6 mVg

100: 5 O. 2 95. 1 1.7

100: 10 5.8 92. 0 1. 4

100: 15 5.6-. 97. 0 0.8

100: 20 6.4 100.0 0.1

(Scralf ⁷ -crushed powder) 4. 4 100. 0 5.1

(Japan Pharmaceutical Sucralfart) 18.6 86.2 1.6 The dispersion particle size of the drug product obtained from Table 2 is similar to the particle size of the powdered sucralfate powder. Showed 100%.

As the mixing ratio of polyethylene glycol to sucralfate increased, granulation progressed, and the specific surface area showed a decreasing trend. From the results of the specific surface area, the granulation was insufficient for the 2.5% additive formulation, and the 20% additive formulation was sufficiently granulated.

Example 3

Sucralfate preparation obtained in Example 2 (sucralfate: polyethylene glycol = 20: 4) 7.2 g of sucrose, 0.4 g of perfume, etc. were added to 92.4 g, and mixed in a plastic bag to obtain fine granules. 100 g of agent were obtained. The obtained fine granules are There was no g, and the ingestibility was good.

The following test was performed to evaluate the binding of sucralfate to plasma protein, which is one of the medicinal effects.

To 5 g of bovine serum albumin (BSA, Sanko Junyaku) was added potassium hydrochloride buffer (approximately pH 1.5) to make 1,000 ml, which was used as the BSA stock solution. The obtained fine granules were weighed in an amount equivalent to 3 Omg as dried sucralfate powder, and dispersed by adding 5 ml of water. Next, 15 ml of the BSA stock solution was added and mixed, followed by shaking at 37 ° C for 30 minutes. Then, add 20 ml of potassium hydrochloride buffer (20 ml) and mix, then filter and separate the insoluble BSA bound to sucralfate using a 0.22 m membrane filter (Millipore), and filter the permeate. And

Take 20 1 of each of the standard solution and the sample solution diluted with the BSA stock solution, add 5 ml of a protein quantification reagent (Protain As say 1 → 5, BioRad), mix and add a spectrophotometer (manufactured by Shimadzu Corporation). The amount of unbound BSA was quantified from the absorbance at 595 nm using the method. BSA _c commercial sucralfate fines was calculated binding constant for the addition amount as BSA binding capacity for (Chugai). Also was measured in the same manner, it was compared with the conventional fine granules. Tables 3 and 4 show the measurement results of the dispersion particle size and BSA binding ability.

[Table 3] Dispersion

Hazard under flat diameter of 50! ^ Fine granules according to the invention 5 丄 100 0% ί¾¾ Fibers 22 0 78 6

[Table 4]

BSA binding ability

Fine granules according to the invention 69.9% (1.5)

¾ ^ Fiber 47.0 (1.0)

() Is the i) agent of 1.0 ^) value, From Tables 3 and 4, the fine granules obtained according to the present invention can be dispersed to 50 m or less, and the BSA binding ability was 1.5 times higher than that of the conventional product.

Example 4

Sucralfate preparation obtained in Example 2 (sucralfate: polyethylene glycol = 20: 4) 360 g was added with 234.6 g of sucrose, 2.4 g of fragrances and the like, and 3 g of a lubricant were added to a V-type mixer (Tsutsui) (Manufactured by RIKEN) to obtain a compounded powder for tablets. The tablets were compressed under pressure using a single-shot tableting machine (manufactured by Kimura Seisakusho) to obtain tablets having a diameter of 18 mm, a flat edge, a tablet weight of 1 g, and a tablet thickness of 3.1 mm.

Tables 5 and 6 show the measurement results of the dispersion particle size and BSA binding ability of the obtained tablets and commercially available alsalmine tablets (registered trademark: manufactured by Chugai Pharmaceutical Co., Ltd.).

[Table 5]

Three

Young girl

Average of 50 in or less

D C

αι

00

[Table 6]

BSA binding ability

Tablets according to the invention 65.1% (2.5)

Follow 26.0 (1.0)

() Is the value when 従 <take U is set to 1.0. From Tables 5 and 6, the dispersed particle size of the tablets obtained by the present invention was as fine as 98% or less at 50 m or less, and the BSA bonding ability was 2.5 times higher than that of the conventional product. L-Zahnaido use mouth ”

From the above results, the sucralfate preparation obtained according to the present invention had a smaller dispersion particle size and a higher binding ability to plasma proteins than the conventional preparation. Therefore, it is possible to remarkably improve the problem of taking and protein binding by the conventional method. The sucralfate preparation obtained by the present invention has excellent characteristics applicable to internal medicine or external medicine such as fine granules, tablets and capsules.

Claims

The scope of the claims

1. A sucralfate preparation obtained by adding 5% by weight or more of a water-soluble low-melting wax to sucralfate and melt-granulating.

2. The preparation according to claim 1, comprising a finely divided sucralfate having a particle size of 50% or less in a proportion of 90% or more and a water-soluble low-melting-point resin.

3. The method according to claim 2, wherein the refined sucralfate has an average particle size of 20 / m or less, and a ratio of the particle size of 5 粒径 zm or less is 90% or more. Formulation.

4. The preparation according to claim 1, 2 or 3, wherein the melting point of the wax is 80 ° C or less.

0 5. The preparation according to claim 4, wherein the wax is polyethylene glycol, polyoxyethylene-polyoxypropylene-glycol or a mixture thereof.

6. The dried sucralfate is pulverized so that the ratio of particles having a particle size of 50 m or less becomes 90% or more, a water-soluble low-melting wax is mixed with the fine particles, and the wax is melted to form sucralfate particles. A method for producing a sucralfate preparation, which is characterized by carrying out adhesion granulation.

7. The method according to claim 6, wherein the water-soluble low-melting-point resin is added and mixed in an amount of 5% by weight or more based on sucralfate.

8. The dry sucralfate according to claim 6 or 07, wherein the dried sucralfate is pulverized so that the ratio of the average particle size is 20 m or less and 50 m or less is 90% or more. Method.

9. The method according to any one of claims 6 to 8, wherein the melting point of the wax is 80 ° C or less.

10. The method according to claim 9, wherein said wax is polyethylene glycol, polyoxyethylene-polyoxypropylene-glycol or a mixture thereof. 51. The method according to any one of claims 6 to 10, wherein an excipient is further added in addition to the wax.